Macrophages respond to infection by intracelluar parasites with increased metabolic, bactericidal and tumoricidal activity. One of the important features of this increased activity or "activation" is an increased potential for generating oxygen radicals, which are important bactericidal agents and which could play an important part in tissue destruction. In order to better understand the relationship between oral bacteria and the phagocytic cells of the host defense system in the pathogenesis of periodontal disease, we will study the effect of a variety of bacterial products on the oxygen radical response of macrophages. Bacterial products to be studied include LPS, muramyl dipeptide and several analogs, and the bone resorption factor isolated from the growth medium of Actinomyces viscosus (ARF). The effects of these bacterial products on "activiation" of macrophages versus osteoclasts will be compared. Further work will be undertaken to characterize ARF and to prepare smaller active fragments by cleavage with specific hydrolytic enzymes. Similar macrophage activating and bone resorbing factors will be sought in the culture media of a variety of gram negative anaerobes, isolated from deep periodontal pockets. Since tese bacterial products cause "macrophage activation" in vitro, they provide the means to study the mechanisms involved. Various chemicals will be tested as possible inhibitors of the activation, in order to determine whether cyclic nucleotides, prostaglandins, methyl carrier proteins, protein phosphorylation, proteolytic cleavage, etc., are involved in regulating macrophage activation. The oxidase enzyme responsible for generating oxygen radicals will be extracted from membrane material and purified. The mechanism of regulation of the enzyme will be investigated by use of inhibitors and protein modification enzymes. An understanding of the mechanisms involved in regulating production of oxygen radicals be macrophages may provide the means to either enhance response to infection or limit tissue destruction in periodontal disease and other inflammatory diseases.